Xanomeline (LY246708) Safety and Efficacy of the Xanomeline Transdermal Therapeutic System (TTS) in Patients with Mild to Moderate Alzheimer's Disease H2Q-MC-LZZT(c) None g/dL U/dL % mg/dL mmol/L µg/mL cm inches U/µL mg/dl M/kg mm/Hg PR g/L µg/dL Units kg A randomized, double-blind, parallel (3 arm), placebo-controlled trial of 26 weeks duration. Indication ASTHMA Screening Epoch Treatment Epoch Follow-Up Epoch Placebo arm Low-dose xanomeline arm (50cm^2 TTS Formulation E, 54 mg xanomeline) High-dose xanomeline arm (75cm^2 TTS Formulation E, 81 mg xanomeline) Screening cell Treatment cell Screening segment/period Treatment segment/period Treatment segment/period Collection of Informed Consent Assignation of Study Participant ID Collection of Medical History Collection of Vital Signs and temperature: Pre-Ambulatory-ECG Placement of Ambulatory ECG Removal of Ambulatory ECG Collection of Vital Signs: Post-Ambulatory-ECG Randomization of the PAtient to a Trial Arm Adverse Event data collection Chest X-Ray as part of screening visit ECG CT scan - if not within last year and patient passes all other screens Concomitant Medications Laboratory (Chem/Hemat) Laboratory (Urinalysis) Plasma Specimen (Xanomeline) Hemoglobin A1C - Performed only if patient is an insulin-dependent diabetic. TTS Acceptability Survey ADAS-Cog CIBIC+ DAD NPI-X Screening Visit 24-Hour Ambulatory ECG Applied ECG Removal, Randomization ECG Results Hachinski Mini-mental State Examination Form Part A: Orientation Stepwise deterioration of cognitive function Abrupt onset of dementia Depression noted on exam Emotional instability during examination Presence/absence of fluctuating mental status Presence/absence of nocturnal confusion Relative preservation of personality Somatic complaints on day of exam Any evidence of atherosclerosis Any focal neurological signs Focal neurological symptoms History of hypertension elicited History of strokes at any time Date on which the informed consent was signed by the subject Unique identifier for the study site; however, SITEID is also unique within a submission. Site ID or Number Subject identifier for the study. Subject ID Unique subject identifier within a submission. Unique subject ID within the submission Investigator identifier. Investigator ID Visit Name / Visit Number. Visit Name / Number Date the visit took place. Visit date Time the visit took place. Visit time General prompt question to aid in monitoring and data cleaning. Has the subject experienced any past and / or concomitant diseases or past surgeries? Pre-printed row number Row number Used to define a category of related records (e.g., CARDIAC or GENERAL). Type of Medical History being collected A categorization of the condition or event pre-printed on the CRF or instructions. Category of Medical History being collected Verbatim or preprinted CRF term for the medical condition or event. Reported Term Verbatim or preprinted CRF term for the medical condition or event. Ongoing? Disease controlled? Disease controlled? A pre-printed prompt used to indicate whether or not a medical condition has occurred. Pre-printed prompt for a specific condition/surgery (e.g., Does the subject have high blood pressure?) Start date of Medical History event. Onset Date End date of Medical History event End Date End date of Medical History event Completion Date Date of measurements Date of Measurements Time of measurements. Time of Vital Sign Measurements Sponsor-defined reference number Sponsor-Defined Identifier Text description of time when measurement should be taken Planned Time Point Verbatim name of the test or examination used to obtain the measurement or finding. {VSTEST} (See Section 2.2.) Vital Sign Test Name Used to indicate that a vital signs measurement was not done. Vitals Status Result of the vital signs measurement as originally received or collected. Vital Sign Test Result or Finding Original units in which the data were collected. Original Units Whether vital sign result was clinically significant. Clinical Significance Location relevant to the collection of Vital Signs measurement. Example: LEFT ARM for blood pressure. Location of Vital Signs Measurement Position of the subject during a measurement or examination. {POSITION} (See Section 2.2.) Position of Subject What year is it? What season is it? What is today's date What day of the week is today What is the month? What state are we in? What county are we in? What town are we in? Can you tell me the name of this hospital? Can you tell me the name of this hospital? What floor of the buidling are we on? Say to the patient "Now I'd like to test your memory... I'm going to name 3 objects. After I have said them, I want you to repeat them. Remember what they are because I'm going to ask you to name them again in a few minutes." Then say the names of the items slowly and clearly. After you have said all objects, ask the patient to repeat them. Also see description. The first repetition determines the score, but keep saying all 3 words (up to 6 trials) until the patient can repeat all 3. One point is given for each correct response - Max. 3 points Instruct the patient: "Begin with 100 and count backwards by 7 and keep subtracting until I tell you to stop." Stop after 5 subtractions (93, 86,79, 72, 65). One point is given for each sequential correct response. If the patient cannot or refuses to perform this test, ask him to spell the "world" backwards. Score 1 point for each letter named in correct order. Ask the patient if he can recall the 3 objects you asked him to remember earlier. Give 1 point for each correct response. Show the patient a wrist and ask "what is this called?". Next show the patient a pencil and ask "what is this called?" Score 1 point for each item named correctly. Ask the patient to repeat this phrase for you: "No if and or buts". Allow only 1 trial. Score 1 point if the phrase is repeated correctly. Have the patient follow this comman, Point to a piece of paper which is on top of the desk and say to the patient: "Please take that piece of paper in your right hand, fold the paper in half with both hands, and put the paper down on the floor". Score 1 point for each segment ("paper in your right hand", "fold the paper in half", "put the paper down on the floor") correctly executed. On a blank piece of paper print the sequence: "Close your eyes", in letters large enough for the patient to see clearly. Ask him to read the words on it and do what it says. Score 1 point if he actually closes his eyes. Gibe the patient a blank piece of paper and ask him to write a sentence for you. Do not dictate a sentence, it has to be written spontaneously. The sentence should have a subject and a verb and make sense. Correct grammar and punctuation are not necessary. Instruct the patient to copy the intersecting pentagons exactly as they are drawn. All 10 angles must be present and 2 must intersect forming a quadrangle to score 1 point. Tremor and rotation are ignored. Used to indicate if the overall physical examination was performed as scheduled. Was the physical examinatio performed? Was the Physical Examination Performed? Date of examination. Date of examination Time of examination. Time of examination Sponsor-defined reference number. Sponsor-Defined Identifier or Line number Name of the body system. Body System Examined Overall assessment of examined body system. Examination Result Text description of any abnormal findings. Abnormal Findings Whether physical examination abnormality is clinically significant Clinical Significance Role of the person who provided the evaluation. Evaluator role Status of whether or not ECG was done. {NY} Indicate if ECG was performed Record the identifier number assigned. ECG Reference ID Method used to measure ECG. {EGMETHOD} Method of ECG Position of the subject during the ECG measurement. Position of the Subject Date of ECG Date of ECG Text description of planned time point when measurements should be taken for use when multiple sequential assessments are done. Planned Time Point Time of ECG Time of ECG Descriptive name of the measurement or finding. ECG Test Name Result of the measurement or finding as originally received or collected. ECG Test Result Original units in which the data were collected. {UNIT} Result Units Whether ECG results were clinically significant. Is the result clinically significant? General prompt question regarding whether or not any AEs were experienced during the study. This provides verification that all other fields on the CRF were deliberately left blank. {NY} (See Section 2.2.) Were any Adverse Events experienced? A sponsor-defined reference number associated with each unique AE record. Line # Verbatim (i.e., investigator-reported term) description of the adverse event. Adverse Event Date when the adverse event started. Start Date Time when the adverse event started. Start Time Date when the adverse event resolved. End Date Time when the adverse event resolved. End Time Indicates AE is ongoing when no End Date is provided. {NY} (See Section 2.2.) Ongoing Description of the severity of the adverse event. {AESEV} (See Section 2.2.) {TOXGR} (See Section 2.2.) Severity Indicates whether or not the adverse event is determined to be “serious” based on what is defined in the protocol. Is the Adverse Event serious? {NY} (See Section 2.2.) Serious Event Indicates if a “serious” adverse event was associated with a congenital anomaly or birth defect. Is the AE associated with a congenital anomaly or birth defect? {NY} (See Section 2.2.) Serious Event Type - Congenital Anomaly or Birth Defect Indicates if a “serious” adverse event was associated with a persistent or significant disability or incapacity. Did the AE result in a persistent or significant disability or incapacity? {NY} (See Section 2.2.) Serious Event Type -Persistent or Significant Disability or Incapacity Indicates if a “serious” adverse event resulted in death. Did the AE result in death? {NY} (See Section 2.2.) Serious Event Type - Death Indicates if a “serious” adverse event resulted in an initial or prolonged hospitalization for the patient. Did the AE result in an initial or prolonged hospitalization for the patient? {NY} (See Section 2.2.) Serious Event Type - Initial or Prolonged Hospitalization Indicates if a “serious” adverse event was life threatening. Is the AE Life Threatening? {NY} (See Section 2.2.) Serious Event Type - Life Threatening Indicates if a “serious” adverse event is associated with other serious or important medical events. Is the AE associated with other serious or important medical events? {NY} (See Section 2.2.) Serious Event Type - Other Serious or Important Medical Events Indication of whether the study treatment had a causal effect on the adverse event, as reported by the clinician/investigator. Relationship to Study Treatment Changes made to the study treatment in response to the adverse event. {ACN} (See Section 2.2.) Action Taken with Study Treatment Describes Other Action(s) taken in response to the adverse event that are unrelated to study treatment dose changes. Other Action Taken Description of the subject’s status associated with an event. {OUT} (See Section 2.2.) Outcome Indication of whether the adverse event caused the subject to discontinue from the study. Did the AE cause the subject to discontinue from the study? {NY} (See Section 2.2.) Adverse Event that Caused Study Discontinuation No Yes Body Frame Size Mean Arterial Pressure Weight Height Heart Rate Pulse Rate Respiratory Rate Systolic Blood Pressure Diastolic Blood Pressure Body Surface Area Body Mass Index: C16358 Adipose Tissue: C12472 Temperature: C25206 Sitting Prone Standing Supine Trendelenburg Reverse Trendelenburg Right lateral decubitus Left lateral decubitus Fowlers Semi-Fowlers Present Absent Present Absent 12 Lead Unspecified 12 Lead Standard 12 Lead Mason Likar 12 Lead Modified Mason Likar 12 Lead Single Pad 12 Lead Non-Standard Standard leads for bicycle exercise. Limb leads on the back (shoulder and on the hips) 12 Lead Cabrera Standard leads one intercostal space higher Frank lead system McFee-Parungao lead system Cube lead system Bipolar uncorrected XYZ lead system Pseudo-orthogonal XYZ lead system 12 Lead EASI Dower Transformation 12 Lead 1 Lead Missing Standard 12-lead and CM5-CC5-CH5 Standard 12-lead and CC5-CM5-ML Standard 12-lead extended to the right by V5R, V4R, V3R Standard 12-lead extended to the left by V7, V8, V9 Vectorcardiograph Corrected Vectorcardiograph Uncorrected Summary (Max) Heart Rate Summary (Mean) PR Duration Summary (Mean) QRS Duration Summary (Mean) QT Duration Summary (Mean) RR Duration Summary (Min) RR Duration Summary (Max) RR Duration Summary (Mean) Heart Rate Summary (Min) Heart Rate QTcB - Bazett's Correction Formula QTcF - Fridericia’s Correction Formula QTcLC - Linear Correction Formula Summary (Mean) JT Interval Summary (Min) JT Interval Summary (Max) JT Interval JTcB - Bazett's Correction Formula JTcF - Fridericia’s Correction Formula JTcLC - Linear Correction Formula Summary (Mean) P Axis Summary (Mean) P Wave Duration Summary (Mean) P Wave Height Summary (Min) PR Duration Summary (Max) PR Duration Summary (Mean) QRS Axis Summary (Min) QT Duration Summary (Max) QT Duration Summary (Mean) R Wave Amplitude Summary (Mean) S Wave Amplitude Summary (Mean) R+S Amplitude Summary (Mean) ST Segment Duration Summary (Mean) T Wave Axis Summary (Mean) T Wave Duration Summary (Mean) T Wave Area Summary (Mean) T Wave Height Summary (Mean) Ventricular Rate Summary (Min) Ventricular Rate Summary (Max) Ventricular Rate Summary (Mean) ST Deviation Summary (Min) ST Deviation Summary (Max) ST Deviation Summary (Mean) ST Elevation Summary (Min) ST Elevation Summary (Max) ST Elevation Summary (Mean) ST Depression Summary (Min) ST Depression Summary (Max) ST Depression Gray Rad Day Hour Percentage Millimeter Kilogram Milligram Milliliter Week Month Year Meter Millisecond Second Ampere Candela Mole Hertz Newton Pascal Joule Watt Coulomb Volt Farad Sievert Ohm Siemens Weber Tesla Henry Degree Celsius Lumen Lux Becquerel Katal Square Meter Cubic Meter Meter Per Second Kilogram per Cubic Meter Degree Fahrenheit pH Microgram Minute Unit of Time Gram Square Centimeter Square Foot Curie Ampule Dosing Unit Bag Dosing Unit Bar Dosing Unit Bolus Dosing Unit Bottle Dosing Unit Box Dosing Unit Can Dosing Unit Capsule Dosing Unit Cartridge Dosing Unit Coat Dosing Unit Container Dosing Unit Cylinder Dosing Unit Disk Dosing Unit Drum Dosing Unit Grain Homeopathic Dilution Unit Implant Dosing Unit Inch Inhalation Dosing Unit Jar Dosing Unit Kallikrein Inhibitor Unit Kit Dosing Unit Liter Lozenge Dosing Unit Microcurie Micromole Micron Millicurie Milliequivalent Millimole Nanogram Nanomole Ounce Package Dosing Unit Packet Dosing Unit Part per Million Patch Dosing Unit Pellet Dosing Unit Percent Weight per Volume Percent Weight per Weight Pouch Dosing Unit Pound Pressor Unit Scoopful Dosing Unit Spray Dosing Unit Strip Dosing Unit Suppository Dosing Unit Syringe Dosing Unit Tablespoon Dosing Unit Tablet Dosing Unit Tampon Dosing Unit Teaspoon Dosing Unit Trace Dosing Unit Troche Dosing Unit Tube Dosing Unit Vial Dosing Unit Wafer Dosing Unit Yard Mole per Liter Percent Volume per Volume International Unit Quantity Sufficient Centimeter Millimeter of Mercury Kilogram per Square Meter Beats per Minute Breaths per Minute Cup Dosing Unit Atmosphere Ring Dosing Unit Millimole per Liter; umol/mL; Micromole per Milliliter; mol/m3; Mole per Cubic Meter Picogram Femtogram Attogram Centigram Dram Kilogram per Liter; g/mL; Gram per Milliliter Gram per Cubic Meter; ug/mL; Microgram per Milliliter; mg/L; Milligram per Liter Milliliters per Minute Gram per Deciliter Picomole Puff Square Millimeter Tuberculin Unit Milliliters per Hour Per Second Per Minute Milligram per Hour Milligram per Deciliter Calorie Kilogram-Calorie Plaque Forming Unit Equivalent Weight High Power Field Gram per Square Meter Microgram per Liter; mg/m3; Milligram per Cubic Meter; ng/mL; Nanogram per Milliliter Low Power Field Millivolt Nanogram per Deciliter Microgram per Cubic Meter Nanometer Osmole Pounds per Square Inch Million International Units Nanocurie International Unit per Liter International Unit per Milliliter; kIU/L; Kilo International Unit per Liter International Unit per Kilogram International Unit per Milligram Liters per Minute Micrograms per Hour Microgram per Kilogram Microkatal per Liter Milligram per Day Milligram per Kilogram Milligram per Square Meter Micromoles per Day Millimeter per Hour Millimole per 24 Hours Nanomole per Liter Picomole per Liter RNA Copies per Milliliter Milliequivalents per Day Milliequivalent Per Liter Milliequivalent Per Kilogram Degree Unit of Plane Angle Decimole Centimole Millimole per Gram Femtomole Attomole Standard Cubic Meter Standard Cubic Foot  Square Inch Enzyme-Linked Immunosorbent Assay Unit Enzyme-Linked Immunosorbent Assay Unit per Dose Enzyme-Linked Immunosorbent Assay Unit per Milliliter Log10 Enzyme-Linked Immunosorbent Assay Unit Log10 Enzyme-Linked Immunosorbent Assay Unit per Dose Mole per Milliliter Millimole per Kilogram Mole per Gram Mole per Milligram Thousand Colony Forming Units Million Colony Forming Units Billion Colony Forming Units Colony Forming Unit per Gram Thousand Colony Forming Units per Gram Million Colony Forming Units per Gram Billion Colony Forming Units per Gram Colony Forming Unit per Milliliter Thousand Colony Forming Units per Milliliter Million Colony Forming Units per Milliliter Billion Colony Forming Units per Milliliter Gauss Kilogram per Square Centimeter Gram per Kilogram; mg/g; Milligram per Gram Part per Thousand Picometer Microliter per Milliliter Nanoliter Drop Mole per Mole Revolution per Minute Dyne Log10 50 Percent Embryo Infective Dose Log10 50 Percent Embryo Infective Dose per Dose Log10 50 Percent Cell Culture Infective Dose Log10 50 Percent Cell Culture Infective Dose per Dose Log10 50 Percent Tissue Culture Infective Dose Log10 50 Percent Tissue Culture Infective Dose per Dose Kilo International Unit International Unit per Gram Anti-Xa Activity International Unit Anti-Xa Activity International Unit per Milliliter Antigen Unit per Milliliter D Antigen Unit D Antigen Unit per Milliliter Allergy Unit per Milliliter Bioequivalent Allergy Unit Tuberculin Unit per Milliliter Millikatal Nanokatal Picokatal Nanokatal per Liter Kilobecquerel Megabecquerel Gigabecquerel Becquerel per Kilogram Becquerel per Gram Becquerel per Microgram; kBq/mg; Kilobecquerel per Milligram; MBq/g; Megabecquerel per Gram Becquerel per Milligram; kBq/g; Kilobecquerel per Gram Gigabecquerel per Gram; kBq/ug; Kilobecquerel per Microgram Gigabecquerel per Microgram; MBq/ug; Megabecquerel per Microgram Gigabecquerel per Milligram; MBq/mg; Megabecquerel per Milligram Curie per Gram; uCi/ug; Microcurie per Microgram; mCi/mg; Millicurie per Milligram Curie per Kilogram; uCi/mg; Microcurie per Milligram; mCi/g; Millicurie per Gram Curie per Microgram Curie per Milligram; mCi/ug; Millicurie per Microgram 50 Percent Embryo Infective Dose 50 Percent Embryo Infective Dose per Dose 50 Percent Cell Culture Infective Dose 50 Percent Cell Culture Infective Dose per Dose 50 Percent Tissue Culture Infective Dose per Dose Microkatal Part per Billion Parts per Trillion Millicurie per Kilogram; uCi/g; Microcurie per Gram Microcurie per Kilogram Roentgen Milliequivalent Per Microliter Milliequivalent Per Gram Milliequivalent Per Microgram Becquerel per Liter Becquerel per Microliter; kBq/mL; Kilobecquerel per Milliliter; MBq/L; Megabecquerel per Liter Becquerel per Milliliter; kBq/L; Kilobecquerel per Liter Kilobecquerel per Microliter; GBq/L; Gigabecquerel per Liter; MBq/mL; Megabecquerel per Milliliter Megabecquerel per Microliter; GBq/mL; Gigabecquerel per Milliliter Curie per Liter; uCi/uL; Microcurie per Microliter Curie per Microliter Curie per Milliliter Microcurie per Liter Millicurie per Liter; uCi/mL; Microcurie per Milliliter Microvolt Cycle per Minute Kilometer International Mile 100 International units/Milliliter Thousand Organisms Million Organisms Billion Organisms Thousand Organisms per Gram Million Organisms per Gram Billion Organisms per Gram Million Organisms per Milligram Billion Organisms per Milligram Thousand Organisms per Milliliter Million Organisms per Milliliter Billion Organisms per Milliliter Plaque Forming Unit per Dose Plaque Forming Unit per Milliliter Bel Gram per Square Centimeter Kilo United States Pharmacopoeia Unit Kilometer Per Hour Nebule Microgram per Day Milligram per Kilogram per Minute International units per Kilogram per Hour Microgram per Kilogram per Minute; Gamma per Kilogram per Minute; gamma/kg/min Micrograms per Minute Foot Fingertip Unit Sachet dosing unit Milligram per Kilogram per Hour Cycle per Second Severe Adverse Event: C41340 Moderate Adverse Event: C41339 Mild Adverse Event:C 41338 Drug Interrupted Dose Not Changed Dose Increased Drug Withdrawn Dose Reduced Not Applicable Unknown Not recovered or not resolved Recovered or Resolved Recovering or Resolving Recovered or resolved with Sequelae Death Related to Adverse Event: C48275 Unknown Over Age 21 Age > 21 Informed Consent Granted Consented = 'true' returns true when the subject is NOT an insulent-dependent diabetic Hachinsky score larger than 4 leading to exclusion MMSE score less than 10 or larger than 23 leading to exclusion